What is the relationship between Allopurinol (Xanthine Oxidase Inhibitor) and Chronic Kidney Disease (CKD)?

From the Guidelines

Allopurinol can be safely used in patients with chronic kidney disease (CKD) and is recommended as the first-line urate-lowering therapy (ULT) for all patients, including those with CKD stage ≥3, starting at a low dose with subsequent dose titration to target. For patients with CKD and hyperuricemia or gout, allopurinol should be initiated at a low dose of ≤100 mg/day, and lower in patients with CKD, with gradual titration upward based on serum uric acid levels and kidney function 1, 2, 3, 4. The maximum dose depends on kidney function, with severely impaired patients (eGFR <30 ml/min) typically not exceeding 200-300 mg daily, while those with better kidney function may reach doses of 300-600 mg daily. Dose adjustments should be made every 2-4 weeks with monitoring of serum uric acid levels, targeting levels below 6 mg/dL. Regular monitoring of kidney function, liver enzymes, and complete blood count is recommended, especially during dose titration. Allopurinol works by inhibiting xanthine oxidase, thereby reducing uric acid production. This mechanism not only helps manage gout but may also reduce oxidative stress and inflammation in the kidneys, potentially slowing CKD progression. Patients should be counseled about possible hypersensitivity reactions, which are rare but more common in those with reduced kidney function, and advised to report any skin rash, fever, or worsening kidney function immediately.

Some key points to consider when using allopurinol in patients with CKD include:

• Starting at a low dose and gradually titrating upward to minimize the risk of adverse effects
• Monitoring serum uric acid levels and adjusting the dose accordingly
• Regularly monitoring kidney function, liver enzymes, and complete blood count
• Counseling patients about possible hypersensitivity reactions and advising them to report any symptoms immediately
• Considering alternative ULT options, such as febuxostat or benzbromarone, if allopurinol is not tolerated or effective.

It's also important to note that the 2020 American College of Rheumatology guideline for the management of gout recommends allopurinol as the preferred first-line ULT for all patients, including those with CKD stage ≥3, and suggests starting at a low dose with subsequent dose titration to target 1, 2, 3, 4. Additionally, the guideline recommends continuing prophylaxis for 3-6 months rather than <3 months, with ongoing evaluation and continued prophylaxis as needed if the patient continues to experience flares 1, 2, 3, 4.

From the FDA Drug Label

In patients with decreased renal function or who have concurrent illnesses which can affect renal function such as hypertension and diabetes mellitus, periodic laboratory parameters of renal function, particularly BUN and serum creatinine or creatinine clearance, should be performed and the patient’s dosage of allopurinol tablets reassessed Patients with decreased renal function require lower doses of allopurinol tablets than those with normal renal function. Lower than recommended doses should be used to initiate therapy in any patients with decreased renal function and they should be observed closely during the early stages of administration of allopurinol tablets In patients with severely impaired renal function or decreased urate clearance, the half-life of oxipurinol in the plasma is greatly prolonged. Therefore, a dose of 100 mg per day or 300 mg twice a week, or perhaps less, may be sufficient to maintain adequate xanthine oxidase inhibition to reduce serum urate levels

Key Considerations for Allopurinol and CKD:

• Patients with decreased renal function require lower doses of allopurinol.
• Dose adjustment is necessary in patients with severely impaired renal function.
• Monitoring of renal function, particularly BUN and serum creatinine or creatinine clearance, is recommended.
• Initiation of therapy should be done with lower than recommended doses in patients with decreased renal function.
• Patients should be observed closely during the early stages of administration of allopurinol tablets [5] [6]

From the Research

Allopurinol and CKD: An Overview

• Allopurinol is a commonly used medication for managing gouty arthritis, but its use in patients with chronic kidney disease (CKD) can be challenging due to the risk of adverse events and uncertain efficacy 7.
• The dosage of allopurinol may need to be reduced in patients with CKD to minimize the risk of toxicity, but this can limit its efficacy in controlling elevated uric acid levels 7, 8.

Efficacy and Safety of Allopurinol in CKD

• Studies have shown inconsistent results regarding the safety and efficacy of allopurinol in patients with CKD, with some trials demonstrating an increased risk of adverse reactions and others not confirming renal insufficiency as a risk factor 8.
• The use of allopurinol in CKD patients has been associated with a potential risk of allopurinol hypersensitivity syndrome, emphasizing the need for careful dose titration and monitoring 8.
• A study comparing the efficacy and safety of low-dose febuxostat and allopurinol in CKD patients found that febuxostat exhibited a superior renal-protective effect and non-inferior safety profile compared to allopurinol 9.

Comparison with Other Urate-Lowering Therapies

• Febuxostat, a novel non-purine selective xanthine oxidase inhibitor, has been shown to be effective in reducing serum uric acid levels in CKD patients and may have a protective effect on the kidneys 9, 10.
• A retrospective study comparing the long-term efficacy and renal safety of febuxostat and allopurinol in CKD patients found that febuxostat was more effective in reducing serum uric acid levels and had a positive effect on renal function 10.

Clinical Considerations

• The management of hyperuricemia in CKD patients requires careful consideration of the potential benefits and risks of urate-lowering therapy, including the use of allopurinol and febuxostat 11.
• Providers should be aware of the potential risks and benefits of allopurinol use in CKD patients and consider alternative therapies, such as febuxostat, in patients who are at high renal risk or have declining renal function 11, 8.